Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster session 01

646P - A phase I trial of AVA6000, a fibroblast activation protein (FAP)-released, tumor microenvironment (TME)-targeted doxorubicin peptide drug conjugate in patients with FAP-positive solid tumors

Date

14 Sep 2024

Session

Poster session 01

Presenters

Christopher Twelves

Citation

Annals of Oncology (2024) 35 (suppl_2): S482-S535. 10.1016/annonc/annonc1589

Authors

C.J. Twelves1, U. Banerji2, W.D. Tap3, N. Cook4, T.R..J. Evans5, R. Plummer6, A. Anthoney7, C. Plummer8, R. Dawson9, P. Loadman10, G. Lahu11, H. Jones10, N. Kinnersley12, R. Edwards13, G. Gordon14, L.D. Cranmer15

Author affiliations

  • 1 Medical Oncology, St. James's University Hospital, LS9 7TF - Leeds/GB
  • 2 Drug Development Unit  , The Institute of Cancer Research and Royal Marsden Hospital, SM2 5PT - Sutton/GB
  • 3 Medical Oncology, MSKCC - Memorial Sloan Kettering Cancer Center, 10065 - New York/US
  • 4 Department Of Medical Oncology, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 5 Institute Of Cancer Sciences, University of Glasgow, G12 8QQ - Glasgow/GB
  • 6 Translational And Clinical Research Institute, Newcastle University, NE1 7RU - Newcastle upon Tyne/GB
  • 7 Institute Of Cancer And Pathology, St. James's University Hospital - Leeds Teaching Hospitals NHS Trust, LS9 7TF - Leeds/GB
  • 8 Cardiology, NUTH - Newcastle Upon Tyne Hospitals NHS Foundation Trust, NE7 7DN - Newcastle-upon-Tyne/GB
  • 9 Medical Oncology, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 10 Pharmacology, University of Bradford, BD7 1DP - Bradford/GB
  • 11 Quantitative Clinical Pharmacology, thinkQ2 AG, 6340 - Baar/CH
  • 12 Biostatistics, Octa Consulting Services Ltd, SW4 0SY - London/GB
  • 13 Translational Medicine, Avacta, W12 7RZ - London/GB
  • 14 Medical Oncology, Avacta, 19312 - BERWYN/US
  • 15 Medical Oncology, Fred Hutchinson Cancer Center, University of Washington, 98109 - Seattle/US

Resources

Login to get immediate access to this content.

If you do not have an ESMO account, please create one for free.

Abstract 646P

Background

AVA6000 is a peptide drug conjugate, in which doxorubicin (dox) is bound by a linker that is specifically cleaved by FAP, which is overexpressed in the TME of many solid tumors.

Methods

The safety, pharmacokinetics (PK) and preliminary efficacy of AVA6000 was studied in a first-in-human, multicenter dose escalation phase I trial. AVA6000 was administered i.v. q3w or q2w using a 3+3 design in patients with locally advanced or metastatic solid tumors categorized as high or middle range FAP (FAPhigh and FAPmid) based on published data. AUC based dosing was used to calculate maximum safe number of cycles of AVA6000 (equivalent to cumulative dox dose of 550mg/m2).

Results

48 pts (median age 60 yr, range 30-79), median 3 prior therapy lines (range, 0-7) received AVA6000 doses of 80 to 385mg/m2 i.v. q3w, and a starting dose of 160mg/m2 given q2w. The safety profile was favorable with both schedules, the most frequent grade 3-4 hematologic toxicities were neutropenia (11%), anemia (6%), and thrombocytopenia (5%). Grade 3 non-hematologic toxicities included mucositis, fatigue and hematemesis (n=1). Two DLTs in the q3w arm were grade 2 cardiac failure (120mg/m2) and grade 4 neutropenia/thrombocytopenia (200mg/m2). Compared to conventional dox, PK showed reduced systemic exposure (AUC, 5-77%) and peak concentration (Cmax, 78-93%), without accumulation suggesting q2w dosing may be optimal. The therapeutic index of free dox was significantly increased, with respect to severe neutropenia, AUC and efficacy. No dose-response relationship was seen between troponin levels and AVA6000 dose. Concentrations of free dox in tumor biopsies (n=11) were ∼2 log scale higher than plasma. PK/PD modeling suggested free dox generation in the TME with an increased plasma distribution half-life. Two PR (RECISTv.1.1) and 3 minor responses (-10 to -29%) were observed in 5 pts with FAPhigh tumor types including salivary gland cancer and soft tissue sarcoma.

Conclusions

AVA6000 delivers high concentration of free dox to the TME relative to plasma, resulting in antitumor activity in FAPhigh tumor types with reduced systemic dox exposure, resulting in lower toxicity versus conventional dox.

Clinical trial identification

NCT04969835.

Editorial acknowledgement

Legal entity responsible for the study

Avacta Group Plc.

Funding

Avacta Group Plc.

Disclosure

All authors have declared no conflicts of interest.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.